Cardiovascular mortality during the past three to four years has plateaued. Among the proposed reasons accounting for this is our limited knowledge of the interaction of the mechanisms enhancing cardiovascular risk. This proposal is designed to address three of these: 1) the renin-angiotensin system (RAS), 2) the plasminogen- activator-inhibitor-1 (PAI-1) system, and 3) the metabolic abnormalities associated with insulin resistance. We have documented potential links in abnormalities in these systems, which are likely to be genetically- determined. Specifically, 1) the RAS profoundly influences vascular response, renal function, and PAI-1 production. 2) An abnormality in the RAS is uniquely associated with insulin resistance. 3) Substantial variations in the occurrence of vascular (pressor, renal and atherosclerotic) and metabolic complications in the hypertensive population may be secondary to variations in the functions of critical genes. Thus, our overall hypothesis is: In hypertension, it is insulin resistance, with differences in the specific alleles of the genes of the RAS and PAI-1 system, that predispose to vascular complications. To evalulate this hypothesis, we will: 1) determine the relationship between insulin sensitivity and the RAS gene profile; 2) test the hypothesis that variation in the pressor and renal hemodynamic responses to angiotensin II (AngII) is mediated by variations in the genetic environment, specifically, the angiotensinogen (AGT) and angiotensin converting enzyme (ACE) genes; 3) assess the relationships between PAI-1 levels, insulin resistance, and the activity of the RAS, and correlate these with PAI-1 and RAS genotypes; and 4) determine the functional significance of polymorphism in the PAI-1 and RAS genes. To accomplish these goals, patients with hypertension will undergo a phenotyping protocol in a controlled environment. Then, mechanistic studies will explore the relationship between the pressor, renal hemodynamic, and PAI-1 responsiveness and the genotypes and insulin resistance. We anticipate that these studies will clarify 1) the relationship between abnormalities in the RAS and insulin resistance, 2) the role of the RAS in mediating the vascular and atherosclerotic (directly and via its effect on the PAI-1 production) complications of human hypertension, and 3) the likelihood that the genetic environment can explain the variable expression of these complications. With this information, specific preventive and therapeutic measures to retard the development of these complications could be proposed and tested in a clinical trial's format.